WO2002050039A1 - Derives d'uree and d'urethanne en tant qu'inhibiteurs de l'integrine - Google Patents

Derives d'uree and d'urethanne en tant qu'inhibiteurs de l'integrine Download PDF

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Publication number
WO2002050039A1
WO2002050039A1 PCT/EP2001/014039 EP0114039W WO0250039A1 WO 2002050039 A1 WO2002050039 A1 WO 2002050039A1 EP 0114039 W EP0114039 W EP 0114039W WO 0250039 A1 WO0250039 A1 WO 0250039A1
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Prior art keywords
acid
ylamιno
formula
ethanoylamιno
compounds
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PCT/EP2001/014039
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English (en)
Inventor
Wolfgang Staehle
Alfred Jonczyk
Oliver Schadt
Simon Goodman
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Merck Patent Gmbh
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Publication date
Priority to AU2002217078A priority Critical patent/AU2002217078A1/en
Priority to CA2431974A priority patent/CA2431974C/fr
Priority to HU0302753A priority patent/HUP0302753A3/hu
Priority to BR0116202-0A priority patent/BR0116202A/pt
Application filed by Merck Patent Gmbh filed Critical Merck Patent Gmbh
Priority to MXPA03005431A priority patent/MXPA03005431A/es
Priority to AT01271360T priority patent/ATE274497T1/de
Priority to KR10-2003-7008122A priority patent/KR20030063432A/ko
Priority to JP2002551536A priority patent/JP4216071B2/ja
Priority to SK818-2003A priority patent/SK8182003A3/sk
Priority to US10/450,855 priority patent/US7135587B2/en
Priority to EP01271360A priority patent/EP1343764B1/fr
Priority to DE60105192T priority patent/DE60105192T2/de
Priority to PL01361745A priority patent/PL361745A1/xx
Publication of WO2002050039A1 publication Critical patent/WO2002050039A1/fr
Priority to NO20032754A priority patent/NO20032754L/no

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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical

Definitions

  • the invention relates to urea and/or urethane derivatives of the formula
  • X is O or NR 5 ,
  • R is H, A, cycloalkyl, Ar, arylalkyl or Pol,
  • R 1 is OR or N(R) 2 ,
  • R 2 and R 3 are each, independently of one another, H, A, Hal, N0 2 , OR,
  • R 5 and R 5' are each, independently of one another, H or A,
  • R 6 is Hal or NO 2 ,
  • R 7 is H, -C(O)R 8 , -C(O)-Ar, R 8 , COOR 8 , COO-(CH 2 ) 0 -Ar, S0 2 -Ar,
  • R b is A or cycloalkyl
  • R 9 is CN or NO 2
  • A is alkyl having 1 to 8 carbon atoms, where the alkyl groups may be monosubstituted or polysubstituted by R 6 and/or their alkyl carbon chain may be interrupted by -0-
  • Ar is phenyl, naphthyl, anthryl or biphenylyl, each of which is unsubstituted or monosubstituted, disubstituted or t ⁇ substi- tuted by A, OH, OA, CN, NO 2 or Hal
  • cycloalkyl is cycloalkyl having from 3 to 15 carbon atoms
  • Pol is a solid phase with no terminal functional group
  • n and m are each, independently of one another, 1 , 2, 3, 4, 5 or 6,
  • the object of the invention was to discover novel compounds having valuable properties, in particular those which are used for the preparation of medicaments
  • the compounds of the formula I and their salts are well tolerated and have very valuable pharmacological properties
  • they act as integ ⁇ n inhibitors, inhibiting, in particular, the interactions of the ⁇ v ⁇ 3 or ⁇ v ⁇ 6 integ ⁇ n receptors with ligands
  • Integ ⁇ ns are membrane-bound, heterodime ⁇ c glycoproteins consisting of an ⁇ subunit and a smaller ⁇ subunit
  • the relative affinity and specificity for ligand binding is determined by recombination of the various ⁇ and ⁇ subunits
  • Particular efficacy is exhibited by the compounds according to the invention in the case of mtegnns ⁇ v ⁇ l , ⁇ v ⁇ 3, ⁇ v ⁇ 5, ⁇ llb ⁇ 3, ⁇ v ⁇ and ⁇ v ⁇ preferably ⁇ v ⁇ 3, ⁇ v ⁇ 5 and ⁇ v ⁇
  • potent selective inhibitors of integ ⁇ n ⁇ v ⁇ 3 and ⁇ v ⁇ very particularly potent selective inhibitors of Integ ⁇ n
  • the compounds of the formula I are able to inhibit the binding of metalloproteinases to mtegnns and thus prevent the cells utilising the enzymatic activity of the proteinase
  • An example can be found in the ability of a cyclo-RGD peptide to inhibit the binding of MMP-2 (mat ⁇ x-metallo- prote ⁇ nase-2) to the vitronectm receptor ⁇ v ⁇ 3, as described in P C Brooks et al , Cell 1996, 85, 683-693
  • tumour cells from a local tumour into the vascular system occurs through the formation of microaggregates (microthromboses) due to the interaction of the tumour cells with blood platelets
  • the tumour cells are masked by the protection in the microaggregate and are not recognised by the immune system cells
  • the microaggregates are able to attach to vessel walls, simplifying further penetration of tumour cells into the tissue Since the formation of microthromboses is promoted by ligand binding to the corresponding integnn receptors, for example ⁇ v ⁇ 3 or ⁇ llb ⁇ 3, on activated blood platelets, the corresponding antagonists can be regarded as effective metastasis inhibitors
  • the compounds of the formula I can be employed as medicament active ingredients in human and veterinary medicine, in particular for the prophylaxis and/or therapy of circulation disorders, thromboses cardiac infarction, arteriosclerosis, apoplexia, angina pectons, tumour diseases such as tumour development or tumour metastasis, osteolytic diseases, such as osteoporosis, pathologically angiogenic diseases, such as, for example, inflammations, opthalmological diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatic arthritis, osteo-arthritis, rubeotic glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, psoriasis, restenosis after angioplasty, multiple sclerosis, viral infection, bacterial infection, fungal infection, in acute kidney failure and in wound healing for supporting the healing process
  • ⁇ v ⁇ 6 is a relatively rare integnn (Busk et al , 1992 J Biol Chem 267(9), 5790) which is increasingly formed in repair processes in epithelial tissue and which preferentially binds the natural matrix molecules fibronect and tenascin (Wang et al , 1996, Am J Respir Cell Mol Biol 15(5), 664)
  • the physiological and pathological functions of ⁇ v ⁇ 6 are not yet known precisely, but it is assumed that this integnn plays an important role in physiological processes and illnesses (for example inflammation, wound healing, tumours) in which epithelial cells are involved
  • ⁇ v ⁇ 6 is expressed on keratmocytes in wounds (Haapasalmi et al , 1996 J Invest Dermatol 106(1 ), 42), from which it can be assumed that, besides wound- healing processes and inflammation, other pathological events in the skin, such as, for example, psoriasis, can also be influenced by
  • the compounds of the formula I can be employed as antimicrobial substances in operations where biological materials, implants, catheters or cardiac pacemakers are used They have an antiseptic action here
  • the efficacy of the antimicrobial activity can be demonstrated by the method described by P Valentm-Weigund et al in Infection and Immunity, 1988 2851 -2855
  • a measure of the uptake of a medicament active ingredient in an organism is its bioavailability
  • the medicament active ingredient is administered to the organism intravenously in the form of an injection solution its absolute bioavailability i e the proportion of the pharmaceutical species which is unchanged in the systemic blood i e enters the general circulation, is 100%
  • the active ingredient is generally in the form of a solid in the formulation and must therefore first dissolve in order that it can overcome the entry barriers for example the gastrointestinal tract, the oral mucous membrane, nasal membranes or the skin, in particular the stratum corneum, and can be absorbed by the body
  • Pharmacokmetic data i e on the bioavailability can be obtained analogously to the method of J Shaffer et al , J Pharm Sciences, 1999, 88, 313-318
  • a further measure of the absorbability of a therapeutic active ingredient is the logD value, since this value is a measure of the lipophihcity of a molecule
  • the compounds of the formula I have at least one centre of chira ty and can therefore occur in a number of stereoisomeric forms All of these forms (for example R- and S-enantiomers) and diastereomers (for example RR- RS-, SR- or SS-forms in the case of compounds having two stereocentres) are included in the formula
  • the compounds according to the invention according to Claim 1 also cover so-called prodrug derivatives, i e compounds of the formula I modified with for example, alkyl or acyl groups, sugars or oligopeptides, which are rapidly cleaved in the organism to give the effective compounds according to the invention
  • solvates of the compounds of the formula I is taken to mean adductions of inert solvent molecules onto the compounds of the formula I which form owing to their mutual attractive force
  • Solvates are, for example mono- or dihydrates or addition compounds with alcohols such as, for example, with methanol or ethanol
  • the invention relates to the compounds of the formula I and their salts and solvates according to Claim 1 and to a process for the preparation of compounds of the formula I and their salts and solvates, characterised in that
  • R 4 and/or R 5 by, for example, i) alkylatmg a hydroxyl group, ii) hydrolys g an ester group to a carboxyl group, in) este fying a carboxyl group, ⁇ v) alkylatmg an ammo group, v) reacting an aryl bromide or iodide with boronic acids by a
  • radicals R 1 to R s , R 5 , B, X and Y are as defined under the stated formulae, unless expressly stated otherwise
  • radicals listed more than once, for example R 5 can have different meanings corresponding to the definition
  • A is alkyl, is linear or branched, and has from 1 to 8, preferably 1 , 2, 3, 4, 5 or 6 carbon atoms
  • A is preferably methyl, furthermore ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, furthermore also pentyl, 1 -, 2- or 3-methylbutyl, 1 ,1-, 1 ,2- or 2,2-d ⁇ methylpropyl, 1 -ethyl- propyl, hexyl, 1 -, 2-, 3- or 4-methylpentyl, 1 ,1-, 1 ,2-, 1 ,3-, 2,2-, 2,3- or 3,3- dimethylbutyl, 1- or 2-ethylbutyl, 1 -ethyl-1 -methylpropyl, 1 -ethyl-2-methyl- propyl, 1 J ,2- or 1 ,2,2-tr ⁇ methylpropyl,
  • Ar is aryl which is unsubstituted or monosubstituted, disubstituted or t ⁇ sub- stituted by A, OH, OA, CN, NO 2 or Hal, where aryl is phenyl, naphthyl, anthryl or biphenylyl Ar is preferably phenyl or naphthyl which is unsubstituted or monosubstituted, disubstituted or tnsubstituted by A, OH, OA, CN, N0 2 or Hal Ar is particularly preferably phenyl
  • Arylalkyl is also -(CH 2 ) X -Ar, where Ar has one of the preferred meanings indicated above and where x may be 1 , 2 or 3 arylalkyl is preferably benzyl, phenylethyl or phenylpropyl, arylalkyl is particularly preferably benzyl
  • Cycloalkyl having from 3 to 15 carbon atoms is preferably cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl cycloalkyl is likewise a monocyclic or bicyclic terpene, preferably p-menthane, menthol pmane, bornane or camphor, where each known stereoisome ⁇ c form is included, or adamantyl For camphor, this is both L-camphor and D-camphor
  • Hal is preferably F, Cl or bromine Hal is particularly preferably Cl
  • Pol is a solid phase with no terminal functional group, as explained in greater detail below
  • the terms solid phase and resin are used synony- mously below
  • the second phenyl radical is preferably coupled to the first phenyl radical in the 3- or 4-pos ⁇ t ⁇ on particularly preferably to the 4-pos ⁇ t ⁇ on of the first phenyl ring
  • X is O or NR , wh .e,re R D 5 has one of the meanings described below
  • R 1 is OR or N(R) 2 , where R has one of the meanings below R 1 is prefer ⁇ ably OR
  • R is H, A, cycloalkyl, Ar, arylalkyl or Pol, where A cycloalkyl, Ar and arylalkyl have one of the meanings described above and Pol has one of the meanings described below
  • R is preferably A, Pol or H R is particularly preferably H or A R is very particularly preferably H
  • Compounds of the formula I in which OR is OPol are in other words polymer-bound compounds of the formula I, in which the acid function is bound to a polymeric support
  • the polymer-bound compounds of the formula I are intermediates in the synthesis of the free acids of the formula I or salts or hydrates thereof
  • R )3 is particularly preferably H, A, Hal, OA or CN, where Hal is particularly preferably F and/or Cl R .3 is very particularly preferably H or Hal
  • R 5 is H or A, where A has one of the meanings given above R 5 is particularly preferably H
  • R 5 is H or A, where A has one of the meanings given above R 5 is particularly preferably H
  • R 6 is Hal or N0 2 , where Hal has one of the meanings given above R 6 is particularly preferably Hal R 7 is preferably H, -C(O)R 8 , -C(O)-Ar, R 8 , COOR 8 , COO-(CH 2 ) 0 -Ar, S0 2 -Ar, S0 2 R 8 or S0 2 -Het, where Ar and Het have one of the meanings indicated above and R 8 is alkyl having from 1 to 10 carbon atoms or cycloalkyl having from 3 to 15 carbon atoms R 7 is preferably H, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl
  • R 8 is alkyl having from 1 to 10 carbon atoms or cycloalkyl having from 3 to 15 carbon atoms, where the terms alkyl and cycloalkyl have one of the meanings described above
  • R 7 is preferably tert-butyl, 2,2-d ⁇ methylpropyl cyclopropyl or cyclohexyl
  • R 9 is CN or N0 2 , particularly preferably CN
  • n and n are each, independently of one another, 1 , 2, 3, 4 5 or 6 m is particularly preferably 2, 3 or 4 m is very particularly preferably 2 n is preferably 1 or 2 n is particularly preferably 1
  • o is 1 , 2, 3 or 4, particularly preferably 1 p is 1 , 2, 3, 4 or 5, particularly preferably 1 or 2, very particularly preferably 1
  • the invention relates in particular to the compounds of the formula I in which at least one of the said radicals has one of the preferred meanings indicated above
  • Some preferred groups of compounds may be expressed by the following sub-formulae la to In, which conform to the formula I and in which the radicals not designated in greater detail have the meaning indicated under the formula I, but in which
  • R is Pol
  • X is NR 5 ;
  • R is H or A
  • Y is -N(R 5 )R 4 ,
  • R 4 is Het
  • R 5 in -N(R 5 ) R 4 is H, m is 2 or 3, n is 1;
  • R isH
  • R 2 is Hal
  • Y is -N(R 5 )R 4
  • R 4 is Het
  • R 5 ⁇ n -N(R 5 )R 4 is H
  • R 1 is OR, R is H or A,
  • Y is -N(R 5 )R 4 ,
  • R 4 is Het
  • R 5 in -N(R 5 )R 4 isH, m is 2 or 3, n is 1;
  • n li R 1 is OR
  • R is H or A
  • R 2 isH
  • R 3 is Hal or A
  • Hal is Cl orF
  • Y is -N(R 5 )R 4 ,
  • R 4 is Het
  • R 5 in -N(R 5 )R 4 is H, m is 2, n is 1,
  • P is 1 or 2;
  • R is H or A
  • R 2 isH
  • R 3 isH
  • Y is -N(R 5 )R 4 , R 4 is Het,
  • Het is pyridin-2-yl or benzimidazol-2-yl, m is 2 or 3, n is 1, o is 1;
  • n Ik R 1 is OR
  • R is H or A
  • X is NR 5 ,
  • Y is -N(R 5 )R 4 ,
  • R 4 is Het
  • R 5 is H, m is 2, 3 or 4, n is 1;
  • R is H or A
  • X is NR S ,
  • Y is -N(R 5 )R 4
  • R 4 is Het
  • R 5 isH, m is 2, 3 or 4, n is 1;
  • R is H or A
  • X is NR 5 ,
  • R 4 is pyr ⁇ d ⁇ n-2-yl or benz ⁇ m ⁇ dazol-2-yl
  • Preferred compounds of the formula I are a) 3-b ⁇ phenyl-4-yl-3- ⁇ 2-[3-(py ⁇ d ⁇ n-2-ylam ⁇ no)propoxycarbonylam ⁇ no]- ethanoylam ⁇ no ⁇ prop ⁇ on ⁇ c acid, b) 3-b ⁇ phenyl-4-yl-3- ⁇ 2-[3-(py ⁇ d ⁇ n-2-ylammo)ethoxycarbonylam ⁇ no]ethanoyl- am ⁇ no ⁇ prop ⁇ on ⁇ c acid, c) 3-(3'-chlorob ⁇ phenyl-4-yl)-3- ⁇ 2-[2-(pyr ⁇ d ⁇ n-2-ylam ⁇ no)ethoxycarbonyl- am ⁇ no]ethanoylam ⁇ no ⁇ prop ⁇ on ⁇ c acid, d) 3-(4'-chlorob ⁇ phenyl-4-yl)-3- ⁇ 2-[2-(py ⁇ d ⁇ n-2-ylam ⁇ no)ethoxycarbon
  • the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but are instead immediately con- verted further into the compounds of the formula I according to Claim 1
  • a plurality of - identical or different - protected ammo and/or hydroxyl groups can be present in the molecule of the starting material If the protecting groups present differ from one another they can in many cases be removed selectively (cf in this respect T W Greene P G M Wuts, Protective Groups in Organic Chemistry, 2nd Edn , Wiley,
  • acyl group is to be understood in the broadest sense in connection with the present process It includes acyl groups derived aliphatic, arali- phatic, alicyclic aromatic and heterocyclic carboxy c acids or sulfonic acids as well as, in particular, alkoxycarbonyl, alkenyloxycarbonyl, aryloxy- carbonyl and especially aralkoxycarbonyl groups Examples of such acyl groups are alkanoyl, such as acetyl
  • hydroxyl protecting group is likewise generally known and relates to groups which are suitable for protecting a hydroxyl group against chemical reactions Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl, aroy
  • TDPS cyclic acetals, such as isopropylidene acetal, cyclopentylidene acetal, cyclohexy dene acetal, benzyhdene acetal, p-methoxybenzy dene acetal and o,p-d ⁇ methoxybenzyl ⁇ dene acetal, acyclic acetals, such as tetrahydropyranyl (Thp), methoxymethyl (MOM), methoxyethoxymethyl (MEM), benzyloxymethyl (BOM) and methylthiomethyl (MTM)
  • Particularly preferred hydroxyl protecting groups are benzyl, acetyl, tert-butyl and TBS
  • the groups BOC and O-tert-butyl may, for example, be removed preferentially using TFA in dichloromethane or using approximately 3 to 5N HCI in dioxane at 15-30°C, and the Fmoc group using an approximately 5 to 50% solution of dimethylamine, diethylamme or pipe ⁇ dine in DMF at 15-30°C
  • the Aloe group can be removed under gentle conditions with noble-metal catalysis in chloroform at 20-30°C
  • a preferred catalyst is tetrak ⁇ s(tr ⁇ phenyl- phosph ⁇ ne)pallad ⁇ um(O)
  • the compounds of the formula I can also be synthesised on a solid phase the binding to the solid phase taking place to R 1
  • R 1 is likewise OPol, NHPol or NRPol
  • Pol is a solid phase without a terminal functional group
  • Pol represents the polymeric support material and all atoms of the anchor group of a solid phase apart from the terminal functional group
  • the anchor groups of a solid phase also known as linkers, are necessary for binding of the compound to be function- alised to the solid phase
  • Compounds of the formula II with R OL, where L is Pol or R,
  • R ⁇ H (formula 11-1 ), are prepared, for example, in accordance with the following reaction scheme 1 , where SGi denotes an amino-protecting group, as described above.
  • the bromophenyl-substituted carboxylic acid 1 is activated in situ by known methods for example by reaction with diisopropylcarbodiimide, and reacted with the alcohol HO-L, where L is as defined above
  • L is as defined above
  • the subsequent coupling of compound 2 to an (R 3 )-subst ⁇ tuted phenylboronic acid under Suzuki conditions generates the biphenyl derivative 3
  • the removal of the protecting group SGi under known conditions liberates a compound of the formula 11-1
  • the Suzuki reaction is advantageously carried out with palladium control, preferably by addition of Pd(PPh 3 ) 4 , in the presence of a base, such as potassium carbonate, in an inert solvent or solvent mixture, for example DMF, at temperatures between 0° and 150°, preferably between 60° and 120°
  • a base such as potassium carbonate
  • an inert solvent or solvent mixture for example DMF
  • the reaction time depending on the conditions used, is between a few minutes and several days
  • the boronic acid derivatives can be pre- pared by conventional methods or are commercially available
  • the reactions can be carried out analogously to the methods indicated in Suzuki et al , J Am Chem Soc 1989, 111 , 314 ff and in Suzuki et al Chem Rev 1995, 95 2457 ff
  • the invention likewise relates to compounds of the formula III in which X, Y, R 5 , R 5 n and m are as defined in Claim 14
  • the coupling reaction preferably succeeds in the presence of a dehydrating agent, for example a carbodnmide, such as dicyclohexylcarbodnmide (DCC), N-(3-d ⁇ methylam ⁇ nopropyl)-N'-ethylcarbod ⁇ m ⁇ de hydrochlo ⁇ de (EDC) or diisopropylcarbodiimide (DIC), furthermore, for example, propane- phosphonic anhydride (cf Angew Chem 1980, 92 129), diphenylphos- phoryl azide or 2-ethoxy-N-ethoxycarbonyl-1 ,2-d ⁇ hydroqu ⁇ nol ⁇ ne, in an inert solvent, for example a halogenated hydrocarbon such as dichloromethane, an ether such as tetrahydrofuran or dioxane, an amide such as DMF or dimethylacetamide, a nit ⁇ le, such as acetonit ⁇ le, in dimethyl
  • de ⁇ va- tives of compounds of the formula III preferably a pre-activated carboxylic acid, or a carboxylic acid hahde, a symmetrical or mixed anhydride or an active ester Radicals of this type for activation of the carboxyl group in typical acylation reactions have been described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-
  • esters are advantageously formed in situ, for example by addition of HOBt (1-hydroxybenzotr ⁇ azole) or N-hydroxy- succinimide
  • the reaction is generally carried out in an inert solvent if a carboxylic acid halide is used, it is carried out in the presence of an acid-binding agent, preferably an organic base, such as tnethylamine, dimethylaniline, pyridine or quino ne
  • an acid-binding agent preferably an organic base, such as tnethylamine, dimethylaniline, pyridine or quino ne
  • alkali or alkaline-earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline-earth metals preferably of potassium, sodium, calcium or caesium
  • a weak acid of the alkali or alkaline-earth metals preferably of potassium, sodium, calcium or caesium
  • a base of the formula I can be converted into the associated acid-addition salt using an acid, for example by reaction of equivalent amounts of the base and the acid in an inert solvent, such as ethanol, followed by evaporation Suitable acids for this reaction are, in particular those which give physiologically acceptable salts
  • inorganic acids for example sulfuric acid, sulfurous acid, dithionic acid, nitric acid hydro- halic acids, such as hydrochloric acid or hydrobromic acid
  • phosphoric acids such as, for example, orthophosphoric acid
  • sulfamic acid furthermore organic acids, in particular aliphatic, alicyclic, araliphatic aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids for example formic acid, acetic acid, propionic acid, hexanoic acid octanoic acid, decanoic acid, hexadecanoic acid, octadecanoic acid, piva c acid,
  • compounds of the formula I can be converted into the corresponding metal salts, in particular alkali metal salts or alkaline earth metal salts, or into the corresponding ammonium salts, using bases (for example sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate)
  • bases for example sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate
  • the invention also relates to the compounds of the formula I according to Claim 1 and their physiologically acceptable salts or solvates as medicament active ingredients
  • the invention furthermore relates to compounds of the formula I according to Claim 1 and their physiologically acceptable salts or solvates as integnn inhibitors
  • the invention also relates to the compounds of the formula I according to Claim 1 and their physiologically acceptable salts or solvates for use in combating illnesses
  • the invention furthermore relates to pharmaceutical preparations comprising at least one compound of the formula I and/or a physiologically acceptable salt or solvate thereof prepared, in particular, by non-chemical methods
  • the compounds of the formula I can be brought into a suitable dosage form here together with at least one solid liquid and/or semi quid excipient or assistant and, if desired, in combination with one or more further active ingredients
  • Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and do not react with the novel compounds for example water, vege- table oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate gelatine carbohydrates, such as lactose or starch, magnesium stearate talc or vaseline
  • Suitable for oral administration are, in particular tablets, pills, coated tablets, capsules, powders, granules syrups juices or drops suitable for rectal administration are supposi
  • the compounds of the formula I and their physiologically acceptable salts or solvates can be used as integnn inhibitors in the combating of illnesses in particular thromboses cardiac infarction, coronary heart diseases arteriosclerosis tumours, osteoporosis, inflammations and infections
  • the compounds of the formula I according to Claim 1 and/or their physiologically acceptable salts are also used in pathological processes which are maintained or propagated by angiogenesis, in particular in tumours reste- noses, diabetic retmopathy, or rheumatoid arthritis
  • the substances according to the invention are generally administered analogously to other known commercially available peptides but in particular analogously to the compounds described in WO 97/26250 preferaoly in doses of from about 0 05 to 500 mg, in particular from 0 5 to 100 mg, per dosage unit
  • the daily dose is preferably from about 0 01 to 2 mg/kg of body weight
  • the specific dose for each patient depends on a wide variety of factors, for example on the efficacy of the specific compound employed on the age, body weight, general state of health sex on the diet, on the time and method of administration on the rate of excretion medicament combination and severity of the particular illness to which the therapy applies Parenteral administration is preferred
  • the compounds of the formula I can be used as integnn ligands for the production of columns for affinity chromatography for the purification of mtegnns
  • the ligand, i e a compound of the formula I is covalently coupled to a polymeric support via an anchor function, for example the carboxyl group
  • Suitable polymeric support materials are the polymeric solid phases having preferably hydrophi c properties that are known in peptide chemistry, for example cross nked polysugars, such as cellulose sepharose or Sephadex R , acrylamides, polyethylene glycol-based polymers or Tentakel R polymers
  • cross nked polysugars such as cellulose sepharose or Sephadex R
  • acrylamides polyethylene glycol-based polymers
  • Tentakel R polymers The materials for affinity chromatography for integnn purification are prepared under conditions as are usual and known per se for the condensation of ammo acids
  • the compounds of the formula I have one or more centres of chira ty and can therefore exist in racemic or optically active form Racemates obtained can be resolved into the enantiomers mechanically or chemically by methods known per se Diastereomers are preferably formed from the racemic mixture by reaction with an optically active resolving agent
  • suitable resolving agents are optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid dibenzoyltarta ⁇ c acid, mandelic acid, malic acid, lactic acid, and the various optically active camphorsulfonic acids, such as ⁇ -camphorsulfonic acid
  • Resolution of the enantiomers with the aid of a column filled with an optically active resolving agent is also advantageous, an example of a suitable eluent is a mixture of hexane/isopropanol/ acetonitnle, for example in the volume
  • optically active compounds of the formula I by the methods described above by using starting materials which are already optically active
  • the eluents used are gradients of acetonitnle (B) with 0 08% of TFA (tnfluoroacetic acid) and water (A) with 0 1 % of TFA The gradient is indicated in per cent by volume of acetonitnle
  • the resin (about 1 g) is stirred at room temperature for 5 hours in a mixture of 1 ml of 4N NaOH, 4 ml of MeOH and 10 ml of dioxane
  • the solid support is filtered off, and the cleavage solution is evaporated to dryness under reduced pressure
  • Example 2 Analogously to Example 1 , the resin "BC" is reacted with ⁇ 3-[2-(pyr ⁇ d ⁇ n-2-yl- am ⁇ no)ethyl]ure ⁇ do ⁇ acet ⁇ c acid (prepared analogously to Example 1 by reaction of N 1 -pyr ⁇ d ⁇ n-2-ylethane-1 ,2-d ⁇ am ⁇ ne dihydrochlonde with 4-n ⁇ tro- phenyl chloroformate and tert-butyl ammoacetate and cleavage of the ester) Cleavage from the support gives 3-b ⁇ phenyl-4-yl-3-(2- ⁇ 3-[2-(pyr ⁇ d ⁇ n- 2-ylam ⁇ no)ethyl]ure ⁇ do ⁇ ethanoylam ⁇ no)prop ⁇ on ⁇ c acid
  • Example 2 Analogously to Example 1 , the resin "BC" is reacted with ⁇ 3-[2-(1 H-benz- ⁇ m ⁇ dazol-2-ylam ⁇ no)ethyl]ure ⁇ do ⁇ acet ⁇ c acid (prepared analogously to Example 1 by reaction of N 1 -(1 H-benz ⁇ m ⁇ dazol-2-yl)ethane-1 ,2-d ⁇ am ⁇ ne dihydrochlonde with 4-n ⁇ trophenyl chloroformate and tert-butyl ammoacetate and cleavage of the ester) Cleavage from the support gives 3-(2- ⁇ 3-[2-(1 H-benz ⁇ m ⁇ dazol-2-ylam ⁇ no)ethyl]ure ⁇ do ⁇ ethanoylam ⁇ no)-3-b ⁇ phenyl-
  • Example 2 Analogously to Example 1 , the resin "BC" is reacted with ⁇ 3-[3-(1 H-benz- ⁇ m ⁇ dazol-2-ylam ⁇ no)propyl]ure ⁇ do ⁇ acet ⁇ c acid (prepared analogously to Example 1 by reaction of N 1 -(1 H-benz ⁇ m ⁇ dazol-2-yl)propane-1 ,3-d ⁇ am ⁇ ne dihydrochlonde with 4-n ⁇ trophenyl chloroformate and tert-butyl amino- acetate and cleavage of the ester) Cleavage from the support gives 3-(2- ⁇ 3-[3-(1 H-benz ⁇ m ⁇ dazol-2-ylam ⁇ no)propyl]ure ⁇ do ⁇ ethanoylam ⁇ no)-3-b ⁇ henyl- 4-ylprop ⁇ on ⁇ c acid
  • Preparative HPLC gives 3-(2- ⁇ 3-[3-(1 H-benz ⁇ m ⁇ dazol-2-yl
  • Example 1 by reaction of N 1 -py ⁇ d ⁇ n-2-ylpropane-1 ,3-d ⁇ am ⁇ ne dihydrochlonde with 4-n ⁇ trophenyl chloroformate and tert-butyl ammoacetate and cleavage of the ester) and cleaved off from the support, giving 3-phenyl-3- (2- ⁇ 3-[3-(pyr ⁇ d ⁇ n-2-ylam ⁇ no)propyl]ure ⁇ do ⁇ ethanoylam ⁇ no)prop ⁇ on ⁇ c acid
  • Example 12 Analogously to Example 1-3, the resin "GH"
  • a solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate in 3 I of bidistilled water is adjusted to pH 6 5 using 2N hydrochloric acid, sterile filtered, transferred into injection vials lyophilised under sterile conditions and sealed under sterile conditions Each injection vial contains 5 mg of active ingredient
  • a mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and allowed to cool Each suppository contains 20 mg of active ingredient
  • a solution is prepared from 1 g of an active ingredient of the formula I, 9 38 g of NaH 2 P0 4 2 H 2 0, 28 48 g of Na 2 HP0 4 12 H 2 0 and 0 1 g of benzalkonium chloride in 940 ml of bidistilled water The pH is adjusted to 6 8, and the solution is made up to 1 I and sterilised by irradiation This solution can be used in the form of eye drops
  • Example D Ointment
  • 500 mg of an active ingredient of the formula I are mixed with 99.5 g of Vaseline under aseptic conditions.
  • a mixture of 1 kg of active ingredient of the formula 1 , 4 kg of lactose, 1 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed to give tablets in a conventional manner in such a way that each tablet contains 10 mg of active ingredient.
  • Tablets are pressed analogously to Example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.
  • each capsule contains 20 mg of the active ingredient.
  • a solution of 1 kg of active ingredient of the formula I in 60 I of bidistilled water is sterile filtered, transferred into ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.
  • Example I Inhalation spray 14 g of active ingredient of the formula I are dissolved in 10 I of isotonic NaCI solution, and the solution is transferred into commercially available spray containers with a pump mechanism The solution can be sprayed into the mouth or nose One spray shot (about 0 1 ml) corresponds to a dose of about 0 14 mg

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Abstract

L'invention concerne des dérivés d'urée et d'uréthanne représentés par la formule générale (I), dans laquelle R?1, R2, R3, R5, R5'¿, X, Y, B, m, n et o sont tels que définis au point 1 des revendications de brevet, y compris les sels ou solvates physiologiquement acceptables correspondants. Il s'agit d'inhibiteurs de l'intégrine susceptibles d'être utilisés pour soigner les maladies suivantes: thrombose, crise cardiaque, maladies coronariennes, artériosclérose, inflammation, tumeurs, ostéoporose, infections et resténose après angioplastie, ou bien processus pathologiques entretenus ou propagés par l'angiogenèse.
PCT/EP2001/014039 2000-12-18 2001-11-30 Derives d'uree and d'urethanne en tant qu'inhibiteurs de l'integrine WO2002050039A1 (fr)

Priority Applications (14)

Application Number Priority Date Filing Date Title
AT01271360T ATE274497T1 (de) 2000-12-18 2001-11-30 Harnstoff- und urethanderivate als integrin inhibitoren
HU0302753A HUP0302753A3 (en) 2000-12-18 2001-11-30 Urea and urethane derivatives as integrin inhibitors, process for their preparation, their use and pharmaceutical compositions containing them
BR0116202-0A BR0116202A (pt) 2000-12-18 2001-11-30 Derivados de uréia e uretano como inibidores de integrinas
JP2002551536A JP4216071B2 (ja) 2000-12-18 2001-11-30 インテグリン阻害剤としての尿素およびウレタン誘導体
MXPA03005431A MXPA03005431A (es) 2000-12-18 2001-11-30 Derivados de urea y uretano como inhibidores de integrina.
CA2431974A CA2431974C (fr) 2000-12-18 2001-11-30 Derives d'uree and d'urethanne en tant qu'inhibiteurs de l'integrine
KR10-2003-7008122A KR20030063432A (ko) 2000-12-18 2001-11-30 인테그린 억제제로서의 요소 및 우레탄 유도체
AU2002217078A AU2002217078A1 (en) 2000-12-18 2001-11-30 Urea and urethane derivatives as integrin inhibitors
SK818-2003A SK8182003A3 (en) 2000-12-18 2001-11-30 Urea and urethane derivative as integrin inhibitor, process for the preparation thereof, its use and pharmaceutical composition comprising same
US10/450,855 US7135587B2 (en) 2000-12-18 2001-11-30 Urea and urethane derivatives as integrin inhibitors
EP01271360A EP1343764B1 (fr) 2000-12-18 2001-11-30 Derives d'uree and d'urethanne en tant qu'inhibiteurs de l'integrine
DE60105192T DE60105192T2 (de) 2000-12-18 2001-11-30 Harnstoff- und urethanderivate als integrin inhibitoren
PL01361745A PL361745A1 (en) 2000-12-18 2001-11-30 Urea and urethane derivatives as integrin inhibitors
NO20032754A NO20032754L (no) 2000-12-18 2003-06-17 Urea- og/eller uretanderivater som integrininhibitorer

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DE10063173A DE10063173A1 (de) 2000-12-18 2000-12-18 Harnstoff- und Urethanderivate
DE10063173.8 2000-12-18

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CZ (1) CZ20031775A3 (fr)
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HU (1) HUP0302753A3 (fr)
MX (1) MXPA03005431A (fr)
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE44681E1 (en) 2006-07-10 2013-12-31 Biogen Idec Ma Inc. Compositions and methods for inhibiting growth of SMAD4-deficient cancers
US8992924B2 (en) 2005-07-08 2015-03-31 Biogen Idec Ma Inc. Anti-ανβ6 antibodies and uses thereof
US9745376B2 (en) 2002-03-13 2017-08-29 Biogen Ma Inc. Anti-ανβ6 antibodies
US10035860B2 (en) 2013-03-15 2018-07-31 Biogen Ma Inc. Anti-alpha V beta 6 antibodies and uses thereof
US10035859B2 (en) 2013-03-15 2018-07-31 Biogen Ma Inc. Anti-alpha V beta 6 antibodies and uses thereof
US11001579B2 (en) 2015-10-23 2021-05-11 Vifor (International) Ag Ferroportin inhibitors
US11129820B2 (en) 2017-04-18 2021-09-28 Vifor (International) Ag Ferroportin-inhibitor salts

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10204789A1 (de) * 2002-02-06 2003-08-14 Merck Patent Gmbh Inhibitoren des Integrins alpha¶v¶beta6
ATE399542T1 (de) * 2003-10-01 2008-07-15 Merck Patent Gmbh Alfavbeta3 und alfavbeta6 integrin antagonisten als antifibrotische mittel
AU2007354317A1 (en) * 2006-10-19 2008-12-04 Biogen Idec Ma Inc. Treatment and prevention of chronic asthma using antagonists of integrin alphaVbeta6
AT509266B1 (de) * 2009-12-28 2014-07-15 Tech Universität Wien Substituierte pyridine und pyrimidine
CN102353728B (zh) * 2011-06-29 2013-03-27 中国食品发酵工业研究院 一种黄酒生产过程质量控制快速检测方法

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WO1996022966A1 (fr) * 1995-01-23 1996-08-01 Biogen, Inc. Inhibiteurs de l'adherence cellulaire
WO1999052493A2 (fr) * 1998-04-16 1999-10-21 Texas Biotechnology Corporation Composes inhibant la fixation d'integrines a leurs recepteurs
WO2000064866A1 (fr) * 1999-04-24 2000-11-02 Astrazeneca Ab Derives diphenylurees

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Publication number Priority date Publication date Assignee Title
DE19939980A1 (de) * 1999-08-24 2001-03-01 Merck Patent Gmbh Inhibitoren des Integrins alphavbeta¶3¶

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996022966A1 (fr) * 1995-01-23 1996-08-01 Biogen, Inc. Inhibiteurs de l'adherence cellulaire
WO1999052493A2 (fr) * 1998-04-16 1999-10-21 Texas Biotechnology Corporation Composes inhibant la fixation d'integrines a leurs recepteurs
WO2000064866A1 (fr) * 1999-04-24 2000-11-02 Astrazeneca Ab Derives diphenylurees

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9745376B2 (en) 2002-03-13 2017-08-29 Biogen Ma Inc. Anti-ανβ6 antibodies
US8992924B2 (en) 2005-07-08 2015-03-31 Biogen Idec Ma Inc. Anti-ανβ6 antibodies and uses thereof
USRE44681E1 (en) 2006-07-10 2013-12-31 Biogen Idec Ma Inc. Compositions and methods for inhibiting growth of SMAD4-deficient cancers
US10035860B2 (en) 2013-03-15 2018-07-31 Biogen Ma Inc. Anti-alpha V beta 6 antibodies and uses thereof
US10035859B2 (en) 2013-03-15 2018-07-31 Biogen Ma Inc. Anti-alpha V beta 6 antibodies and uses thereof
US11001579B2 (en) 2015-10-23 2021-05-11 Vifor (International) Ag Ferroportin inhibitors
US11066399B2 (en) 2015-10-23 2021-07-20 Vifor (International) Ag Ferroportin inhibitors
AU2016342309B2 (en) * 2015-10-23 2021-10-21 Vifor (International) Ag Ferroportin inhibitors
US11129820B2 (en) 2017-04-18 2021-09-28 Vifor (International) Ag Ferroportin-inhibitor salts

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DE60105192T2 (de) 2005-09-08
KR20030063432A (ko) 2003-07-28
SK8182003A3 (en) 2003-10-07
AR035608A1 (es) 2004-06-16
DE10063173A1 (de) 2002-06-20
NO20032754D0 (no) 2003-06-17
ZA200305550B (en) 2004-10-18
EP1343764B1 (fr) 2004-08-25
PL361745A1 (en) 2004-10-04
EP1343764A1 (fr) 2003-09-17
NO20032754L (no) 2003-06-17
ES2227063T3 (es) 2005-04-01
RU2003121015A (ru) 2005-02-10
US7135587B2 (en) 2006-11-14
BR0116202A (pt) 2003-12-23
DE60105192D1 (de) 2004-09-30
CA2431974A1 (fr) 2002-06-27
DK1343764T3 (da) 2004-12-06
US20040063644A1 (en) 2004-04-01
CZ20031775A3 (cs) 2003-09-17
JP2004516282A (ja) 2004-06-03
HUP0302753A2 (hu) 2003-12-29
ATE274497T1 (de) 2004-09-15
CN1481364A (zh) 2004-03-10
MXPA03005431A (es) 2003-09-10
CA2431974C (fr) 2010-08-17

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